Penetration enhancers for transdermal delivery of systemic agent

ABSTRACT

This invention relates to a method for administering systemically active agents including therapeutic agents through the skin or mucosal membranes of humans and animals in a transdermal device or formulation comnprising topically administering with said systemic agent an effective amount of a membrane penetration enhancer having the structural formula ##STR1## wherein X represents sulfur, oxygen or 2 hydrogen radicals; Y represents --CH 2  --, --NH-- or oxygen; n and m are integers of from 1 to 3; p is an integer of from 3 to 17; wherein p≧9; q is 2, 4, 6 or 8; and R&#39; is selected from the group consisting of H, a lower alkyl group having from 1 to 4 carbon atoms, phenyl, lower alkyl or halogen substituted phenyl, acetamido, halogen, piperidinyl, lower alkyl or halogen substituted piperidinyl, carbalkoxy, carboxamide, and alkanoyl.

REFERENCE TO EARLIER FILED APPLICATIONS

This application is continuation-in-part of U.S. Ser. No. 103,445, entitled COMPOSITIONS COMPRISING 1-OXO-OR THIOHYDROCARBYL SUBSTITUTED AZACYCLOALKANES, filed on Sept. 30, 1987.

BACKGROUND OF THE INVENTION

(1.) Field of the Invention

The invention generally relates to an improved method of drug delivery. More particularly, the invention relates to an improved membrane penetration enhancer for use in the transdermal delivery of systemically active drugs to humans and animals.

(2.) Background of the Prior Art

For some years, pharmaceutical researchers have sought an effective means of introducing drugs into the bloodstream by applying them to unbroken skin. Among other advantages, such administration can provide a comfortable, convenient, and safe way of giving many drugs now taken orally or infused into veins or injected intramuscularly.

Using skin as the portal for drug entry offers unique potential, because transdermal delivery permits close control over drug adsorption. For example, it avoids factors that can cause unpredictable absorption from the gastrointestinal tract, including: changes in acidity, motility, and food content. It also avoids initial metabolism of the drug by the liver. Thus, controlled drug entry through skin can achieve a high degree of control over blood concentrations of drug.

Close control over drug concentrations in blood can translate readily into safer and more comfortable treatment. When a drug's adverse effects occur at higher concentrations than its beneficial ones, rate control can maintain the concentrations that evoke only--or principally--the drug's desired actions. This ability to lessen undesired drug actions can greatly reduce the toxicity hazards that now restrict or prevent the use of many valuable agents.

Transdermal delivery particularly benefits patients with chronic disease. Many such patients have difficulty following regimens requiring several doses daily of medications that repeatedly cause unpleasant symptoms. They find the same drugs much more acceptable when administered in transdermal systems that require application infrequently--in some cases, only once or twice weekly--and that reduce adverse effects.

Transdermal delivery is feasible for drugs effective in amounts that can pass through the skin area and that are substantially free of localized irritating or allergic effects. While these limitations may exclude some agents, many others remain eligible for transdermal delivery. Moreover, their numbers will expand as pharmaceutical agents of greater potency are developed. Particularly suitable for transdermal delivery are potent drugs with only a narrow spread between their toxic and safe blood concentrations, those having gastrointestinal absorption problems, or those requiring frequent dosing in oral or injectable form.

Transdermal therapy permits much wider use of natural substances such as hormones. Often the survival times of these substances in the body are so short that they would have to be taken many times daily in ordinary dosage forms. Continuous transdermal delivery provides a practical way of giving them, and one that can mimic the body's own patterns of secretion.

At present, controlled transdermal therapy appears feasible for many drugs used for a wide variety of ailments including, but not limited to, circulatory problems, hormone deficiency, respiratory ailments, and pain relief.

Percutaneous administration can have the advantage of permitting continuous administration of drug to the circulation over a prolonged period of time to obtain a uniform delivery rate and blood level of drug. Commencement and termination of drug therapy are initiated by the application and removal of the dosing devices from the skin. Uncertainties of administration through the gastrointestinal tract and the inconveniences of administration by injection are eliminated. Since a high concentration of drug never enters the body, problems of pulse entry are overcome and metabolic half-life is not a factor of controlling importance.

U.S. Pat. Nos. 3,989,815; 3,989,816; 3,991,203; 4,122,170; 4,316,893; 4,415,563; 4,423,040; 4,424,210; and 4,444,762 generally describe a method for enhancing the topical (as contrasted to the systemic) administration of physiologically active agents by combining such an agent with an effective amount of a penetration enhancer and applying the combination topically to humans or animals, in the form of creams, lotions, gels, etc.

Penetration enhancers for enhancing systemic administration of therapeutic agents transdermally are cited in U.S. Pat. Nos. 4,405,616; 4,462,075; 4,031,894, 3,996,934; and 3,921,636.

SUMMARY OF THE INVENTION

It has been discovered that the penetration enhancers previously disclosed in U.S. patent application Ser. No. 103,445 filed on Sept. 30, 1987, to enhance topical delivery of physiologically active agents also enhance the transdermal delivery of systemically active agents through the skin or other body membranes of humans and animals directly into the bloodstream.

The invention therefore provides a method for topically administering systemically active agents through the skin or mucosal membranes of humans and animals, utilizing a transdermal device or formulation, wherein the improvement in said method comprises topically administering with said systemic agent an effective amount of a membrane penetration enhancer having the general structural formula: ##STR2## wherein X may represent oxygen, sulfur or 2 hydrogen radicals; Y may represent --CH₂ --, --NH-- or oxygen; n and m are integers of from 1 to 3; p is an integer of from 3 to 17; q is 2, 4, 6 or 8; wherein p is ≧9; and R' is selected from the group consisting of H, a lower alkyl group having from 1 to 4 carbon atoms, phenyl, lower alkyl or halogen substituted phenyl, acetamido, halogen, piperidinyl, carbalkoxy, carboxamide, and alkanoyl; Preferably , R' is H, at least the X on the side chain is oxygen and the X on the ring is oxygen or 2 hydrogen radicals and q is 2. In a more preferred embodiment of the present invention, p is 4-16, e.g. 10.

The invention also provides an improved method for administering systemically active therapeutic agents topically through the skin of humans in a transdermal device or formulation to obtain therapeutic blood levels of the therapeutic agent, wherein the improvement in said method comprises the use of an effective skin penetration enhancing amount of the above membrane penetration enhancer, with said therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

The unsaturated 1-oxohydrocarbyl-substituted derivatives of azacycloalkanes, useful in the method of the present invention include compounds represented by the general formula: ##STR3## wherein r is an integer of from 2-6 and p and q are defined above.

Many of these 1-oxohydrocarbyl-substituted derivatives, useful as penetration-enhancing additives in the compositions of the instant invention, are well known. They may be made by the methods described in U.S. patent application 103,445, filed on Sept. 30, 1987. Typical examples of compounds represented by the above general formula that effect systemic penetration include:

N-(1-oxododec-10-enyl)morpholine

2', 6'-dimethyl-N-(1-oxohexadec-10-enyl)morpholine

2', 6'-dimethyl-N-(1-oxooctadec-10-enyl)morpholine

2', 6'-dimethyl-N-(1-oxododec-10-enyl)morpholine

2', 6'-dimethyl-N-(1-oxotridec-11-enyl)morpholine

2', 6'-dimethyl-N-(1-oxotetradec-12-enyl)morpholine

2', 6'-dimethyl-N-(1-oxoundec-10-enyl)morpholine

N-(1-oxooctadec-17-enyl)morpholine

N-(1-oxonon-8-enyl)morpholine

N-(1-oxodec-9-enyl)morpholine

N-(1-oxododec-10-enyl)morpholine

N-(1-oxohexadec-15-enyl)morpholine

N-(1-oxotetradec-13-enyl)morpholine

N-(1-oxooct-7-enyl)morpholine

N-(1-oxohex-5-enyl)morpholine

N-(1-oxohept-6-enyl)morpholine

N-(1-oxoopent-4-enyl)morpholine

N-(1-oxoundec-2-enyl)morpholine

N-(1-oxodeca-2,3-dienyl)morpholine

N-(1-oxononadec-18-enyl)morpholine

N-(1-oxoundec-10-enyl)morpholine

N-(1-oxoheptadec-15-enyl)morpholine

N-(1-oxopentadec-14-enyl)morpholine

2,6-dimethyl-4-(1-oxodec-17-enyl)morpholine

N-(1-oxotridec-12-enyl)morpholine

N-(1-oxododec-10-enyl)azacycloheptane

2,6-dimethyl-N-(1-oxohexadec-10-enyl) azacycloheptane

2,6-dimethyl-N-(1-oxooctadec-10-enyl)azacycloheptane

2,6-dimethyl-N-(1-oxododec-10-enyl)azacycloheptane

2,6-dimethyl-N-(1-oxotridec-11-enyl)azacycloheptane

2,6-dimethyl-N-(1-oxotetradec-12-enyl)azacycloheptane

2,6-dimethyl-N-(1-oxoundec-10-enyl)azacycloheptane

N-(1-oxooctadec-17-enyl)azacycloheptane

N-(1-oxonon-8-enyl)azacycloheptane

N-(1-oxodec-9-enyl)azacycloheptane

N-(1-oxododec-10-enyl)azacycloheptane

N-(1-oxohexadec-15-enyl)azacycloheptane

N-(1-oxotetradec-13-enyl)azacycloheptane

N-(1-oxopentadec-14-enyl)azacyclohept-2-one

2,6-dimethyl-N-(1-oxodec-17-enyl)azacyclohept-2-one

N-(1-oxotridec-12-enyl)azacyclohept-2-one

Typical systemically active agents which may be delivered transdermally are therapeutic agents which are sufficiently potent that they can be delivered through the skin or other membrane to the bloodstream in sufficient quantities to produce the desired therapeutic effect. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives, such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, anthelmintics, antiarthritics, antiasthma agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, including gastrointestinal and urinary; anticholinergics, sympathomimetics, xanthine derivatives, cardiovascular preparions including calcium channel blockers, beta-blockers, antiarrhythmics, antihypertensives, diuretics, vasodialators including general, coronary, peripheral and cerebral; central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, psychostimulants, sedatives and tranquilizers.

Dosage forms for application to the skin or other membranes of humans and animals include creams, lotions, gels, ointments, suppositories, sprays, aerosols, buccal and sub-lingual tablets and any one of a variety of transdermal devices for use in the continuous administration of systemically active drugs by absorption through the skin, oral mucosa or other membranes, see, for example, one or more of U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,742,951; 3,814,097; 3,921,636; 3,972,995; 3,993,072; 3,993,073, 3,996,934; 4,031,894; 4,060,084; 4,069,307; 4,201,211; 4,230,105; 4,292,299 and 4,292,303. U.S. Pat. No. 4,077,407 and the foregoing patents also disclose a variety of specific systemically active agents which may also be useful in transdermal delivery, which disclosures are hereby incorporated herein by this reference.

Typical inert carriers which may be included in the foregoing dosage forms include conventional formulating materials, such as, for example, water, isopropyl alcohol, gaseous fluorocarbons, ethyl alcohol, polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producing materials such as "Carbopol", stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, "Polysorbates", "Tweens", sorbital, methylcellulose, etc.

Systemically active agents are used in amounts calculated to achieve and maintain therapeutic blood levels in a human or animal over the period of time desired. These amounts vary with the potency of each systemically active substance, the amount required for the desired therapeutic or other effect, the rate of elimination or breakdown of the substance by the body once it has entered the bloodstream and the amount of penetration-enhancer in the formulation. In accordance with conventional prudent formulating practices, a dosage near the lower end of the useful range of a particular agent is usually employed initially and the dosage increased or decreased as indicated from the observed response, as in the routine procedure of the physician.

The amount of penetration enhancer which may be used in the invention varies from about 1 to 100 percent although adequate enhancement of penetration is generally found to occur in the range of about 1 to 100 percent although adequate enhancement of penetration is generally found to occur in the range of about 1 to about 10 percent by weight of the formulation to be delivered. The penetration-enhancer disclosed herein may be used in combination with the active agent or may be used separately as a pre-treatment of the skin or other body membrane though which the systemically-active agent is intended to be delivered.

The invention is further illustrated by the following examples which are illustrative of a specific mode of practicing the invention and is not intended as limiting the scope of the appended claims.

EXAMPLE 1

A composition, in the form of a gel, suitable for transdermal delivery of haloperidol, an antidyskinetic or antipsychotic drug, is prepared by mixing the following components in the given concentration.

    ______________________________________                                         Component               Weight %                                               ______________________________________                                         Haloperidol             1-5                                                    N--(1-Oxoundec-10-enyl) 1-10                                                   azacycloheptan-2-one                                                           Carbopol 934 P          0.5-2                                                  (Available from B. F. Goodrich)                                                Neutralizing Agent (NaOH)                                                                              q.s.                                                   Tween-20                1-10                                                   (Available from Atlas Chemical,                                                a Div. of I.C.I.)                                                              Preservative            q.s.                                                   (Sorbic Acid)                                                                  Antioxidant             q.s.                                                   (Ascorbic Acid)                                                                Chelating Agent         q.s.                                                   (Disodium salt of                                                              ethylenediaminetetraacetic acid)                                               Deionized Water         q.s. to 100                                            ______________________________________                                    

This composition is topically applied to the skin of a human subject and after the passage of a suitable period of time haloperidol is found in the bloodstream of said subject.

EXAMPLE 2

When an amine, e.g., triethylamine or triethanolamine, is substituted for NaOH the results are substantially similar, i.e., a topical composition suitable for transdermally delivering haloperidol to the bloodstream is obtained.

EXAMPLE 3

When potassium sorbate, or a lower alkyl paraben, e.g., methyl, ethyl, propyl, or butyl paraben are substituted for the preservative of the composition of Example 1, the results are substantially similar, i.e., a topical composition suitable for the transdermal delivery of haloperidol to the bloodstream is obtained.

EXAMPLE 4

When ascorbyl palmitate, Vitamin E, thioglycerol, thioglycolic acid, sodium formaldehyde sulfoxylate, BHA, BHT, propyl gallate or sodium metabisulfite are substituted for the antioxidant of the composition formulated in Example 1, the results are substantially similar in that a topical composition suitable for transdermally delivering haloperidol to the bloodstream is obtained.

EXAMPLE 5

The composition of Example 1 is prepared in the form of a sodium alginate gel by mixing the following components in the following given concentrations:

    ______________________________________                                         Component              Weight %                                                ______________________________________                                         Haloperidol            1-5                                                     N--(1-oxoundec-10-enyl)                                                                               1-10                                                    azacycloheptan-2-one                                                           Sodium Alginate        0.5-5                                                   Calcium Salts          q.s.                                                    Tween-20               1-10                                                    Preservative*          q.s.                                                    Antioxidant**          q.s.                                                    Chelating Agent***     q.s.                                                    Deionized Water        to 100                                                  ______________________________________                                          *Suitable preservatives are those used in Example 3 as well as sorbic          acid.                                                                          **Suitable antioxidants are those used in Example 4 including ascorbic         acid.                                                                          ***The chelating agent is the disodium salt of ethylenediaminetetraacetic      acid.                                                                    

This composition when applied topically is found to transdermally deliver haloperidol to the bloodstream of a subject.

EXAMPLE 6

The composition of Example 1 is prepared in the form of a hydrophilic cream by mixing the following components.

    ______________________________________                                         Component              Weight %                                                ______________________________________                                         Oil Phase                                                                      Cetyl Alcohol          5-15                                                    Stearyl Alcohol        1-5                                                     N--(1-oxoundec-10-enyl)                                                                               0.5-10                                                  azacycloheptan-2-one                                                           Glycerol Monostearate  2-7                                                     Water Phase                                                                    Sodium Laurylsulfate   0.1                                                     Solvent*               2-20                                                    Tween-20               1-5                                                     Water                  q.s. to 100                                             ______________________________________                                          *Suitable solvents are propylene glycol, glycerin, alcohols, for example,      ethyl alcohol, isopropyl alcohol, etc., and polyethylene glycols.        

The oil phase and the water phase is made up separately, and then agitated to form an emulsion. (When, as in Example 8, the active ingredient, is other than haloperidol, depending on its lipophilicity, it will be distributed in the oil or water phase.) This hydrophilic cream, when applied topically to the skin of a human, is found to transdermally deliver haloperidol into the bloodstream.

EXAMPLE 7

The composition of the instant invention may also be delivered by use of a polymeric matrix. For example, a solid polymer such as cellulose triacetate, polyvinyl acetate, terpolymers and copolymers of polyvinyl alcohol and polyvinyl acetate, and silicon elastomers is imbibed with a liquid having the following components in the given concentrations.

    ______________________________________                                         Component              Weight %                                                ______________________________________                                         Polymer                5-40                                                    Haloperidol            q.s.                                                    N--(1-oxoundec-10-enyl)                                                                               0.5-80                                                  azacycloheptane-2-one                                                          Solvent*               5-90                                                    Surfactant**           1-10                                                    Preservative***        q.s.                                                    Antioxidant****        q.s.                                                    ______________________________________                                          *Solvents may be the solvents used in Example 6 above.                         **The Surfactant may be Tween20, glycerol monostearate or sodium               laurylsulfate, etc.                                                            ***The preservative may be any of the preservatives used in Example 3          above.                                                                         ****The antioxidants may be any of those used in Example 4 above.        

When solid matrix, containing the active ingredients formulated above, is contacted with the skin of a human subject, after a period of time the active agent is found in the bloodstream of said subject.

EXAMPLE 8

Examples 1 to 7 are repeated except that the following active ingredients in the given concentrations are substituted for haloperidol:

    ______________________________________                                         Active Ingredient     Weight %                                                 ______________________________________                                         Isosorbide Dinitrate  5-15                                                     Nitroglycerin         1-5                                                      Estradiol             1-5                                                      Clonidine             0.5-3                                                    Propranolol           1-5                                                      Indomethacine         5-15                                                     Nifedipine            1-5                                                      Nicardipine           1-5                                                      Diclorofenac          5-15                                                     Metaproterenol        1-5                                                      ______________________________________                                    

Similar results are obtained in that the active ingredient is transdermally delivered to the bloodstream of an animal.

EXAMPLE 9

Examples 1 to 8 are repeated except that the compounds exemplified on page 7 (except for N-(1-oxoundec-10-enyl) azacycloheptan-2-one are substituted for N-(1- oxoundec-10-enyl)azacycloheptan-2-one. Similar results are obtained in that the active ingredients are transdermally delivered to the bloodstream of an animal.

N-(1-oxoundec-10-enyl)azacycloheptane and N-(1-oxoundec-10-enyl)morpholine are specially suitable for substituted for N-1-oxoundec-10pl -enyl)azacycloheptane-2-one in Examples 1 to 8.

While particular embodiments of the invention have been described it will be understood of course that the invention is not limited thereto since many obvious modifications can be made and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims. 

Having now described the invention, we claim:
 1. A method for topically enhancing penetration of systemically active agents through the skin or mucosal membranes of humans and animals and into the bloodstream, wherein said method comprises the topical administration of an effective amount of a systemically active agent and an effective systemic penetrating amount of a membrane penetration enhancer having the structural formula ##STR4## wherein X represents sulfur, oxygen or 2 hydrogen radicals; Y represents --CH₂ --, --NH--or oxygen; n and m are integers of from 1 to 3; p is an integer of from 3 to 17; wherein p≧9; q is 2, 4, 6 or 8; and R' is selected from the group consisting of H, a lower alkyl group having from 1 to 4 carbon atoms, phenyl, lower alkyl or halogen substituted phenyl, acetamido, halogen, piperidinyl, lower alkyl or halogen substituted piperidinyl, carbalkoxy, carboxamide, and alkanoyl.
 2. The method in claim 1 wherein p is between 4 and
 16. 3. The method of claim 2 wherein p is
 10. 4. The method of claim 1 wherein the systemically active agent is a therapeutic agent.
 5. The method of claim 4 wherein the administration is concurrent.
 6. The method of claim 1 wherein the membrane penetration enhancer is selected from the group consisting of N-(1-oxoundec-10-enyl)azacycloheptane-2-one, N-(1-oxoundec-10-enyl)azacycloheptane and N-(1-oxoundec-10-enyl)morpholine.
 7. The method of claim 1 wherein the systemically active agent is selected from the group consisting of haloperidol, isosorbide dinitrate, nitrogycerin, estradiol, clonidine, propranolol, indomethacin, nifedipine, nicardipine, diclorofenac and metaproterenol.
 8. The method of claim 8 wherein the systemically active agent is selected from the group consisting of haloperidol, isosorbide dinitrate, nitroglycerin, estradiol, clonidine, propranolol, indomethacin, nifedipine, nicardipine, diclorofenac and metaproterenol.
 9. A method for topically administering an effective amount of a systemic physiologically active agent to a human or animal comprising administering to a human or animal an effective amount of a physiologically active systemic agent and a non-toxic systemically penetrating amount of penetration-enhancing agent represented by the general formula ##STR5## wherein r is an integer of from 2-6, p is an integer of from 3 to 17 and q is
 2. 10. The method of claim 9 wherein the systemically active agent is selected from the group consisting of N-(1-oxoundec-10-enyl)azacycloheptane-2-one, N-(1-oxoundec-10-enyl)azacycloheptane and N-(1-oxoundec-10-enyl)morpholine.
 11. The method of claim 9 wherein the systemically active agent is a therapeutic agent.
 12. The method of claim 10 wherein the systemically active agent is selected from the group consisting of haloperidol, isosorbide dinitrate, nitroglycerin, estradiol, clonidine, propranolol, indomethacin, nifedipine, nicardipine, diclorofenac and metaproterenol.
 13. The method of claim 9 wherein the systemically active agent is selected from the group consisting of haloperidol, isosorbide dinitrate, nitroglycerin, estradiol, clonidine, propranolol, indomethacin, nifedipine, nicardipine, diclorofenac and metaproterenol. 